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出境医 / 临床实验 / Deep Brain Stimulation for Tinnitus

Deep Brain Stimulation for Tinnitus

Study Description
Brief Summary:
Tinnitus is the perception of a sound in the absence of an audible source. Currently up to 15% of the general population suffers chronically from tinnitus. The most severe degree of tinnitus ís experienced by 2.4% of the population and is associated with insomnia, depression; anxiety and even suicide. Up to date there is no effective standard therapy. Current therapies mostly focus on treating the distress caused by tinnitus instead of reducing the actual phantom sound. Nevertheless, many patients do not benefit from the current approaches and become severe and chronic tinnitus sufferers. In these patients neuromodulation-based treatments can be a promising option. Tinnitus perception is associated with many complex changes in several different brain structures. The general accepted hypothesis is that neuronal changes occur in both auditory and non-auditory brain structures, most often as a compensating mechanism on reduced input from the auditory nerve caused by cochlear hair cell damage. These central neuronal changes include an increase in spontaneous firing rate, synchronized activity, bursting activity and tonotopic reorganization. In high-frequency deep brain stimulation (DBS) a reversible lesion-like effect is mimicked. From findings in Parkinson's disease patients who also had tinnitus and were treated with DBS, it is known that stimulation can alter or even completely diminish perception of tinnitus. It can be expected that modulation of specific structures within the complex tinnitus pathways can disrupt pathological neuronal activity and thereby alter tinnitus perception or distress caused by this phantom sensation. The investigators found in animal studies that DBS in the central auditory pathway can indeed significantly decrease tinnitus-like behavior. In a questionnaire study the investigators found that around one-fifth of the patients would be reasonably willing to accept invasive treatments and one-fifth would be fully willing to undergo invasive treatment like DBS. Based on preclinical studies and human case studies, the investigators expect that DBS of the central auditory pathway will inhibit tinnitus perception and distress caused by this phantom sensation. Based on studies performed within Maastricht University Medical Center (MUMC), the investigators selected the medial geniculate body of the thalamus (MGB) as the most potential target to treat tinnitus with DBS.

Condition or disease Intervention/treatment Phase
Tinnitus Device: Deep Brain Stimulation Not Applicable

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 6 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Clinical intervention study (double blind, randomized cross-over design). Two different stimulation paradigms will be investigated: ON and OFF stimulation.
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Deep Brain Stimulation for Refractory Tinnitus
Estimated Study Start Date : December 2020
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : December 2022
Arms and Interventions
Arm Intervention/treatment
Experimental: ON-OFF
Patients receive the same baseline, a 6 week period of stimulation ON (masked for both patient and investigator), one week of washout, a 6 week period of stimulation OFF (masked for both patient and investigator), one week of washout, a 6 month follow-up period of open-label stimulation ON.
Device: Deep Brain Stimulation
High frequency deep brain stimulation in the medial geniculate body of the thalamus.

Experimental: OFF-ON
Patients receive the same baseline, a 6 week period of stimulation OFF (masked for both patient and investigator), one week of washout, a 6 week period of stimulation ON (masked for both patient and investigator), one week of washout, a 6 month follow-up period of open-label stimulation ON.
Device: Deep Brain Stimulation
High frequency deep brain stimulation in the medial geniculate body of the thalamus.

Outcome Measures
Primary Outcome Measures :
  1. Change over time of the score on the Tinnitus Functional Index [ Time Frame: Week 1, week 20, week 26, week 33, week 60 ]
    A validated questionnaire which assesses the impact of tinnitus on a patient measured on multiple time points to measure a change over time. The TFI score can range from 0-100, higher values indicate more tinnitus burden. When a patient scores 54 or higher the tinnitus is considered to be a major problem.


Secondary Outcome Measures :
  1. VAS Loudness [ Time Frame: Week 1, week 12, week 20, week 26, week 33, week 60 ]
    on a scale from 0 (no tinnitus) to 10 (most severe tinnitus imaginable), subjects rate their tinnitus perception on loudness.

  2. VAS Burden [ Time Frame: Week 1, week 12, week 20, week 26, week 33, week 60 ]
    on a scale from 0 (no tinnitus) to 10 (most severe tinnitus imaginable), subjects rate their tinnitus perception amount of discomfort.

  3. 15 word memory test [ Time Frame: Week 1, week 27, week 34, week 60 ]
    Participants are given a list of 15 unrelated words repeated over five different trials and are asked to repeat. Another list of 15 unrelated words are given and the client must again repeat the original list of 15 words and then again after 30 minutes.

  4. Boston naming test [ Time Frame: Week 1, week 27, week 34, week 60 ]
    The neurpsychologist shows the person each of the pictures, one at a time in the given order. The person is given 20 seconds to say what the drawing depicts.

  5. Stroop Color and Word Test [ Time Frame: Week 1, week 27, week 34, week 60 ]
    This is a neuropsychological test used to assess the ability to inhibit cognitive interference that occurs when the processing of a specific stimulus feature impedes the simultaneous processing of a second stimulus attribute, well-known as the Stroop Effect.

  6. Trail Making Test [ Time Frame: Week 1, week 27, week 34, week 60 ]
    This is a neuropsychological test of visual attention and task switching. It consists of two parts in which the subject is instructed to connect a set of 25 dots as quickly as possible while still maintaining accuracy.

  7. Semantic Verbal Fluency Test (Animals) [ Time Frame: Week 1, week 27, week 34, week 60 ]
    This is a test in which participants have to produce as many words as possible from a category, here animals.

  8. Semantic Verbal Fluency Test (Jobs) [ Time Frame: Week 1, week 27, week 34, week 60 ]
    This is a test in which participants have to produce as many words as possible from a category, here jobs.

  9. Phonemic Verbal Fluency Test (D) [ Time Frame: Week 1, week 27, week 34, week 60 ]
    This is a test in which participants have to produce as many words as possible from a category, here words starting with the letter D.

  10. Phonemic Verbal Fluency Test (A) [ Time Frame: Week 1, week 27, week 34, week 60 ]
    This is a test in which participants have to produce as many words as possible from a category, here words starting with the letter A.

  11. Phonemic Verbal Fluency Test (T) [ Time Frame: Week 1, week 27, week 34, week 60 ]
    This is a test in which participants have to produce as many words as possible from a category, here words starting with the letter T.

  12. Quality of life Questionnaire [ Time Frame: Week 1, week 27, week 34, week 60 ]
    The Short Form (36) Health Survey (standard validated questionnaire)

  13. Beck Depression Inventory II (BDI-II) [ Time Frame: Week 1, week 60 ]
    Validated questionnaire for depression.

  14. Beck Anxiety Inventory (BAI) [ Time Frame: Week 1, week 60 ]
    Validated questionnaire for anxiety.

  15. Hospital Anxiety and Depression Scale (HADS) [ Time Frame: Week 1, week 60 ]
    Validated questionnaire for anxiety and depression.

  16. Audiometry [ Time Frame: Week 1, week 14, week 27, week 34, week 60 ]
    pure-tone and speech audiometry. These are the clinical standard audiometric tests.

  17. Auditory Brainstem Response [ Time Frame: Week 1, week 14, week 27, week 34, week 60 ]
    Neurophysiological measure following standard protocols.

  18. Electroencephalography (EEG) [ Time Frame: Week 1, week 14, week 27, week 34, week 60 ]
    Neurophysiological measure following standard protocols.

  19. Local Field Potentials (LFP) [ Time Frame: Week 12 ]
    Neurophysiological measure following standard protocols.


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years to 69 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Medically refractory tinnitus. Patient does not respond to available tinnitus treatments (hearing aids, cognitive treatments) and is thoroughly evaluated by the multidisciplinary tinnitus team in MUMC. Thus patients do not respond to both of the following treatments (i.e. TQ is still ≥ 47):
  • Hearing aids (except if hearing is normal)
  • Evidence-based cognitive treatment in Hoensbroek (Cima et al., 2012) or a similar version of this treatment in the MUMC
  • Minimum age 18 years, maximum age 69 years.
  • Experiencing tinnitus which is:
  • Not pulsatile
  • Unilateral or bilateral
  • Severe tinnitus (based on the TQ score ≥ 47)
  • Chronic and stable (present > 2 years and stable > 1 year).
  • Bilateral hearing of high tone Fletcher Index < 60 dB
  • Willingness to participate in this study (informed consent)

Exclusion Criteria:

  • Anatomic cause of tinnitus (e.g. vestibular schwannoma, tumour, middle-ear pathology)
  • DSM-V psychiatric disorders, other than depression or anxiety disorder (such as bipolar disorder, dementia, addiction, personality disorders); diagnosed by a psychiatrist. A psychiatrist will screen the patients for this matter.
  • Depression or anxiety disorder which was already present before tinnitus. A psychiatrist will screen the patients for this matter.
  • Cognitive impairment (assessed with standard 'cognitive functioning battery test' questionnaires) or coping problems (CISS-21)
  • Active ear diseases that needs further attention according to research team
  • Pregnancy or breast-feeding
  • Active suicide thoughts or attempts
  • Underlying malignancies, whenever life expectancy is lower than 2 years
  • Other implantable electronic devices that potentially could interfere with DBS, e.g. cochlear implants, auditory brainstem implants or cortical implants
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Jana Devos, Drs. +31644936611 jana.devos@maastrichtuniversity.nl
Contact: Jasper Smit, Dr. jasper.smit@maastrichtuniversiy.nl

Sponsors and Collaborators
Maastricht University Medical Center
Investigators
Layout table for investigator information
Principal Investigator: Mark Janssen, Dr. Maastricht University Medical Center
Tracking Information
First Submitted Date  ICMJE March 7, 2019
First Posted Date  ICMJE June 6, 2019
Last Update Posted Date March 23, 2020
Estimated Study Start Date  ICMJE December 2020
Estimated Primary Completion Date December 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 4, 2019)
Change over time of the score on the Tinnitus Functional Index [ Time Frame: Week 1, week 20, week 26, week 33, week 60 ]
A validated questionnaire which assesses the impact of tinnitus on a patient measured on multiple time points to measure a change over time. The TFI score can range from 0-100, higher values indicate more tinnitus burden. When a patient scores 54 or higher the tinnitus is considered to be a major problem.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 4, 2019)
  • VAS Loudness [ Time Frame: Week 1, week 12, week 20, week 26, week 33, week 60 ]
    on a scale from 0 (no tinnitus) to 10 (most severe tinnitus imaginable), subjects rate their tinnitus perception on loudness.
  • VAS Burden [ Time Frame: Week 1, week 12, week 20, week 26, week 33, week 60 ]
    on a scale from 0 (no tinnitus) to 10 (most severe tinnitus imaginable), subjects rate their tinnitus perception amount of discomfort.
  • 15 word memory test [ Time Frame: Week 1, week 27, week 34, week 60 ]
    Participants are given a list of 15 unrelated words repeated over five different trials and are asked to repeat. Another list of 15 unrelated words are given and the client must again repeat the original list of 15 words and then again after 30 minutes.
  • Boston naming test [ Time Frame: Week 1, week 27, week 34, week 60 ]
    The neurpsychologist shows the person each of the pictures, one at a time in the given order. The person is given 20 seconds to say what the drawing depicts.
  • Stroop Color and Word Test [ Time Frame: Week 1, week 27, week 34, week 60 ]
    This is a neuropsychological test used to assess the ability to inhibit cognitive interference that occurs when the processing of a specific stimulus feature impedes the simultaneous processing of a second stimulus attribute, well-known as the Stroop Effect.
  • Trail Making Test [ Time Frame: Week 1, week 27, week 34, week 60 ]
    This is a neuropsychological test of visual attention and task switching. It consists of two parts in which the subject is instructed to connect a set of 25 dots as quickly as possible while still maintaining accuracy.
  • Semantic Verbal Fluency Test (Animals) [ Time Frame: Week 1, week 27, week 34, week 60 ]
    This is a test in which participants have to produce as many words as possible from a category, here animals.
  • Semantic Verbal Fluency Test (Jobs) [ Time Frame: Week 1, week 27, week 34, week 60 ]
    This is a test in which participants have to produce as many words as possible from a category, here jobs.
  • Phonemic Verbal Fluency Test (D) [ Time Frame: Week 1, week 27, week 34, week 60 ]
    This is a test in which participants have to produce as many words as possible from a category, here words starting with the letter D.
  • Phonemic Verbal Fluency Test (A) [ Time Frame: Week 1, week 27, week 34, week 60 ]
    This is a test in which participants have to produce as many words as possible from a category, here words starting with the letter A.
  • Phonemic Verbal Fluency Test (T) [ Time Frame: Week 1, week 27, week 34, week 60 ]
    This is a test in which participants have to produce as many words as possible from a category, here words starting with the letter T.
  • Quality of life Questionnaire [ Time Frame: Week 1, week 27, week 34, week 60 ]
    The Short Form (36) Health Survey (standard validated questionnaire)
  • Beck Depression Inventory II (BDI-II) [ Time Frame: Week 1, week 60 ]
    Validated questionnaire for depression.
  • Beck Anxiety Inventory (BAI) [ Time Frame: Week 1, week 60 ]
    Validated questionnaire for anxiety.
  • Hospital Anxiety and Depression Scale (HADS) [ Time Frame: Week 1, week 60 ]
    Validated questionnaire for anxiety and depression.
  • Audiometry [ Time Frame: Week 1, week 14, week 27, week 34, week 60 ]
    pure-tone and speech audiometry. These are the clinical standard audiometric tests.
  • Auditory Brainstem Response [ Time Frame: Week 1, week 14, week 27, week 34, week 60 ]
    Neurophysiological measure following standard protocols.
  • Electroencephalography (EEG) [ Time Frame: Week 1, week 14, week 27, week 34, week 60 ]
    Neurophysiological measure following standard protocols.
  • Local Field Potentials (LFP) [ Time Frame: Week 12 ]
    Neurophysiological measure following standard protocols.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Deep Brain Stimulation for Tinnitus
Official Title  ICMJE Deep Brain Stimulation for Refractory Tinnitus
Brief Summary Tinnitus is the perception of a sound in the absence of an audible source. Currently up to 15% of the general population suffers chronically from tinnitus. The most severe degree of tinnitus ís experienced by 2.4% of the population and is associated with insomnia, depression; anxiety and even suicide. Up to date there is no effective standard therapy. Current therapies mostly focus on treating the distress caused by tinnitus instead of reducing the actual phantom sound. Nevertheless, many patients do not benefit from the current approaches and become severe and chronic tinnitus sufferers. In these patients neuromodulation-based treatments can be a promising option. Tinnitus perception is associated with many complex changes in several different brain structures. The general accepted hypothesis is that neuronal changes occur in both auditory and non-auditory brain structures, most often as a compensating mechanism on reduced input from the auditory nerve caused by cochlear hair cell damage. These central neuronal changes include an increase in spontaneous firing rate, synchronized activity, bursting activity and tonotopic reorganization. In high-frequency deep brain stimulation (DBS) a reversible lesion-like effect is mimicked. From findings in Parkinson's disease patients who also had tinnitus and were treated with DBS, it is known that stimulation can alter or even completely diminish perception of tinnitus. It can be expected that modulation of specific structures within the complex tinnitus pathways can disrupt pathological neuronal activity and thereby alter tinnitus perception or distress caused by this phantom sensation. The investigators found in animal studies that DBS in the central auditory pathway can indeed significantly decrease tinnitus-like behavior. In a questionnaire study the investigators found that around one-fifth of the patients would be reasonably willing to accept invasive treatments and one-fifth would be fully willing to undergo invasive treatment like DBS. Based on preclinical studies and human case studies, the investigators expect that DBS of the central auditory pathway will inhibit tinnitus perception and distress caused by this phantom sensation. Based on studies performed within Maastricht University Medical Center (MUMC), the investigators selected the medial geniculate body of the thalamus (MGB) as the most potential target to treat tinnitus with DBS.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:
Clinical intervention study (double blind, randomized cross-over design). Two different stimulation paradigms will be investigated: ON and OFF stimulation.
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Tinnitus
Intervention  ICMJE Device: Deep Brain Stimulation
High frequency deep brain stimulation in the medial geniculate body of the thalamus.
Study Arms  ICMJE
  • Experimental: ON-OFF
    Patients receive the same baseline, a 6 week period of stimulation ON (masked for both patient and investigator), one week of washout, a 6 week period of stimulation OFF (masked for both patient and investigator), one week of washout, a 6 month follow-up period of open-label stimulation ON.
    Intervention: Device: Deep Brain Stimulation
  • Experimental: OFF-ON
    Patients receive the same baseline, a 6 week period of stimulation OFF (masked for both patient and investigator), one week of washout, a 6 week period of stimulation ON (masked for both patient and investigator), one week of washout, a 6 month follow-up period of open-label stimulation ON.
    Intervention: Device: Deep Brain Stimulation
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: June 4, 2019)
6
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2022
Estimated Primary Completion Date December 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Medically refractory tinnitus. Patient does not respond to available tinnitus treatments (hearing aids, cognitive treatments) and is thoroughly evaluated by the multidisciplinary tinnitus team in MUMC. Thus patients do not respond to both of the following treatments (i.e. TQ is still ≥ 47):
  • Hearing aids (except if hearing is normal)
  • Evidence-based cognitive treatment in Hoensbroek (Cima et al., 2012) or a similar version of this treatment in the MUMC
  • Minimum age 18 years, maximum age 69 years.
  • Experiencing tinnitus which is:
  • Not pulsatile
  • Unilateral or bilateral
  • Severe tinnitus (based on the TQ score ≥ 47)
  • Chronic and stable (present > 2 years and stable > 1 year).
  • Bilateral hearing of high tone Fletcher Index < 60 dB
  • Willingness to participate in this study (informed consent)

Exclusion Criteria:

  • Anatomic cause of tinnitus (e.g. vestibular schwannoma, tumour, middle-ear pathology)
  • DSM-V psychiatric disorders, other than depression or anxiety disorder (such as bipolar disorder, dementia, addiction, personality disorders); diagnosed by a psychiatrist. A psychiatrist will screen the patients for this matter.
  • Depression or anxiety disorder which was already present before tinnitus. A psychiatrist will screen the patients for this matter.
  • Cognitive impairment (assessed with standard 'cognitive functioning battery test' questionnaires) or coping problems (CISS-21)
  • Active ear diseases that needs further attention according to research team
  • Pregnancy or breast-feeding
  • Active suicide thoughts or attempts
  • Underlying malignancies, whenever life expectancy is lower than 2 years
  • Other implantable electronic devices that potentially could interfere with DBS, e.g. cochlear implants, auditory brainstem implants or cortical implants
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 69 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Jana Devos, Drs. +31644936611 jana.devos@maastrichtuniversity.nl
Contact: Jasper Smit, Dr. jasper.smit@maastrichtuniversiy.nl
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03976908
Other Study ID Numbers  ICMJE NL67027.068.18
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Maastricht University Medical Center
Study Sponsor  ICMJE Maastricht University Medical Center
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Mark Janssen, Dr. Maastricht University Medical Center
PRS Account Maastricht University Medical Center
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP